CN87107599A - 4-hydroxyl-4-(substituted alkenyl base) hexahydrobenzoic acid - Google Patents
4-hydroxyl-4-(substituted alkenyl base) hexahydrobenzoic acid Download PDFInfo
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Abstract
The present invention relates to and have the active compound of antagonism leukotrienes, they are: 4-hydroxyl-4-alkane thiazolinyl cyclohexane carboxylic acid derivative.These compounds can be used for treating allergic disorder, particularly aspect treatment patient's asthma.They are to obtain by suitable oxa-spiro compound and mercapto-chain alkyl acid derivative prepared in reaction.
Description
The present invention relates to one group of compound, that is: 4-hydroxyl-4-(substituted alkenyl base) hexahydrobenzoic acid and its derivative.Say exactly, the present invention relates to compound with following general structure.
N is one from 0 to 2 a integer in the formula, and R is a straight chained alkyl that contains 6 to 15 carbon atoms, and X is hydrogen atom (when n is 1 or 2, X also can be amino), Y is-OH ,-OR
*(R
*Represent low alkyl group) ,-NH
2,-NHR
*,-NR
2 *Or
(R ' be the alkyl or the benzyl of H, 1 to 4 carbon atom), Z be OH ,-OR
*,-NH
2,-NHR
*Or-NR
2 *Y can be identical with Z, and is also different, but they are normally identical.Low alkyl group above-mentioned is meant the alkyl that contains 1 to 4 carbon atom.
Compound for given has steric isomerism.Above shown in chemical structural formula be believed to comprise various possible steric isomers, wherein also contain this steric isomer of (outward) racemic mixture.More precisely, because the substituting group in the said structure is to be connected on the cyclohexane ring with single bonded form, like this, two isomer just may occur on each interface, cyclohexane ring planar above and below is different each other to cause owing to substituting group is in for it.Yet, given at the 1-of cyclohexane ring and the compound of 4-substd, perhaps there is plane symmetry, like this, the number of possible steric isomer will reduce.Consider there are two keys that may occur (suitable-anti-) isomery how much, this depends on R group position with respect to this molecule remainder in double bond structure.Usually, (outward) racemization isomer mixture obtains than single optically active isomer is easier.So that mentioned in this application and obtained, except explanation specially, will be understood that it is (outward) racemization isomer mixture.At this, for a compound, absolute configuration is determined.What it showed usually is the main optically active isomer that contains in a small amount of mixture of enantiomers.
Above-mentioned low alkyl group is meant the alkyl that contains 1 to 4 carbon atom.For example: methyl, ethyl, propyl group and butyl, this definition equally also is applicable to the low alkyl group of mentioning later.And the alkyl group that letter r is represented is octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl.
In the treatment suitable by above-mentioned acid (as one of Y in the structural formula and Z or the two be-during OH) salt that forms, be also included within the scope of the invention.These subsalt comprise the sodium known in this area, potassium, calcium, magnesium, triethylamine, Trimethylamine 99, dicyclohexylamine etc., but are not limited to these compounds.These subsalt can obtain with the free acid among the present invention and the suitable alkali method by standard.Yet the compound of preferentially selecting for use in the present invention is that Y and Z are those compounds of hydroxyl simultaneously in the structural formula.
Provide examples of compounds of the present invention below:
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-(2-propyloic) sulfo-)-2-cetene base-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (4 α, 4 β, 4(Z)))-4-(1-(carboxymethyl) sulfo--2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-vaccenic acid base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-tetradecene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((carbamoyl methyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-(3-carboxylic propyl group) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-(1 α, 4 β, 4(Z))-4-(1-(2-amino-2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((N-carboxymethyl) carbamoyl methyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-(N-(1-carboxylic butyl) carbamoyl methyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-(N-(1-carboxyl-2-styroyl) carbamoyl methyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((carbamoyl methyl) sulfo-)-2-cetene base)-4-hydroxyl hexanaphthene Carboxylamide.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((N-methylamino formyl methyl) sulfo-)-2-cetene base)-4-hydroxy-n-methylcyclohexane Carboxylamide.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-(N, N-diethylamino formyl methyl) sulfo-)-2-cetene base)-the 4-hydroxy-n, N-diethyl cyclohexane Carboxylamide.
(4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(S)-and (1 α, 4 α, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(1 α, 4 α, 4(Z))-(±)-4-(1-(2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(1 α, 4 β, 4(Z))-(±)-4-(1-((2-carboxymethyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(1 α, 4 β, 4(E))-(±)-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(4(S)-(1 α, 4 β, 4(E))-4-(1-((methylol) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
Compound among the present invention is with the epoxide in the following formula.
The definition of R is with noted earlier consistent in the formula, and Z ' is-OR
*,-NH
2,-NHR
*Or-NR
2 *
With the mercapto-chain alkyl acid derivative in the following formula
N is one from 0 to 2 a integer in the formula, and X ' is hydrogen atom (when n was 1 or 2, X can be Q-NH-also, and Q is the amido protecting group in the formula).Y ' is-OR
*,-NH
2,-NHR
*,-NR
2 *Or
(R ' be hydroxyl, alkyl, the benzyl of 1 to 4 carbon atom), Y " is-OR
*
React in appropriate solvent and under the condition that has alkali to exist, also can follow-up following steps: " or Z ' be-OR as Y ', Y
*The time, " or Z is-those compounds of OH earlier with strong mineral alkali processing, and then use the strong acid acidifying, just to obtain Y in the following formula, Y.Although Y ' is normally identical in above-mentioned reaction reagent with Z ', they also can be different.It is not so difficult to reach this point, if by suitable choosing then reaction reagent just can roll into a ball and cause difference in sour palace.When between Y ' in the product and Z ' group, have one be the fat group words (promptly-OR
*).Obviously, this group can provide corresponding free carboxylic acid groups by the further hydrolysis of standard method.
Although when X is-NH
2The time; blocking group is not essential; but amino group often passes through the blocking group of certain standard; be protected with amino acid whose form; trifluoroacetyl group is a kind of better protecting group; hydrolysis can when leaving away, Y or Z fat group take place with it; form a free amino; benzyloxy carbonyl acyl also is a useful blocking group; although the condition that its hydrolysis needs is stronger than trifluoroacetyl group; yet carbobenzoxy-(Cbz) also can be removed by shortening, and it does not influence any other locational ester group in molecule.
The alkali that uses in epoxide open loop process is a tertiary amine preferably, as: triethylamine, the solvent that reacts used should be the molten reaction reagent of a kind of energy, but for reaction itself, has the inert solvent, low chain alkanol is a solvent preferably, especially low-level chain triacontanol be used in reaction in the alcohol moiety of ester when corresponding.Therefore, concerning methyl esters, should make solvent and concerning ethyl ester, should make solvent with methyl alcohol with ethanol.
The ester of back and alkaline saponification and the mixing salt acidifying that generates provided corresponding free acid all are the standard methods on the organic chemistry, therefore need not elaborate to used reaction reagent and reaction conditions.
In above-mentioned general method,, can make by a series of suitable reactions from available raw material as the epoxide of initial reactant.For example: the 4-methyl hydroxybenzoate is by making catalyzer with the aluminium sesquioxide that contains 5% rhodium, and hydrogenation provides 4-hydroxyl hexanaphthene methyl benzoate.Product is then used the pyridinium chlorochromate oxidation, obtains 4-oxo hexahydrobenzoic acid methyl esters.The Homologation that 4-oxo hexahydrobenzoic acid methyl esters is carried out 2 carbon generates 4-(oxo ethylidene)-the hexahydrobenzoic acid methyl esters is to be undertaken by the method that A.I.Meyers sets up.With diisopropylamine lithium acetaldehyde is closed the metallization of uncle's fourth imines earlier, handle with diethyl chloro-phosphate again, obtain amine lithium phosphoric acid salt (Lithioeneaminephosphonate) and add 4-oxo hexahydrobenzoic acid methyl esters, then acid hydrolysis just obtains 4-(oxo ethylidene) the hexahydrobenzoic acid methyl esters.With this oxidation ethylidene compound of sodium borohydride reduction, obtain the 4-(2-hydroxy ethylidene) the hexahydrobenzoic acid methyl esters.
This hydroxy ethylidene compound is transformed into desired epoxide intermediates, available following series reaction explanation.
More precisely, by using known Sharpless asymmetric Epoxidation technology, in building-up process, introduced chirality herein at this place.For example: handle hydroxy ethylidene with (+)-diethyl tartrate, different third titanium oxide (IV) and the tert-butylhydroperoxide, obtain two kinds of isomer, the 2-(methylol)-(3(S)-suitable or trans)-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.The compound that indicates cis is taked known Swern oxidation technology, with oxalyl chloride, dimethyl sulfoxide (DMSO) and triethylamine oxidation, obtains 2-formyl-(3(S)-cis)-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.This compound carries out the Witting olefination with alkyl three phenyl phosphonium bromides and potassium tert.-butoxide, obtains the 2-(1-thiazolinyl)-(3(S)-(3 α, 3(Z), 6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.In the described in front epoxidation process, use (-)-diethyl tartrate just to obtain two other 2-methylol isomer, then, they carry out above-mentioned reaction again, obtain 3(R)-isomer.
In these examples, desired final product is an acid amides, and these compounds can obtain in said process by using suitable reagent.On the other hand, as previously mentioned, the ester that the present invention obtains also can be transformed into corresponding amide by reaction with ammonia or a suitable amine.
At the used special conditions of said process, in all embodiment of back, done detailed narration.
Compound among the present invention can be used for treating allergic disorder, particularly treats segmental bronchus, asthma aspect.For example: SRS-A(late response supersensitivity material) be considered to a kind of in the allergy bronchial asthma very important media.Exactly, SRS-A is a kind of in target tissue inside or the top layer is synthetic and the material that discharges.Exactly,, stimulate in case be subjected to suitable antibody because people's segmental bronchus is responsive especially to SRS-A, at once will be in the transformation reactions target tissue inside of sensitivity or the top layer synthetic and discharge the SRS-A material.
Therefore, can resist the material of SRS-A effect, can be used for treating bronchial asthma disease.
Up-to-date studies confirm that late response material (SRS-A) actual be a kind of mixture of the peptidyl-leukotrienes that is described.LTD
4Be a kind of of these leukotrienes, and regard it as their representative so long, in general, the antagonistic action of the antagonistic action of this material and late response material is similar.Particularly the resulting compound of the present invention can be used as LTD
4Antagonist, so they can be used for treating allergic disorder, especially treat bronchial asthma disease, they filter out according to its antagonistic action, are suppressing aspect histamine and the carbechal, they are not considered to competitive.
The compound activity of gained of the present invention can be illustrated by following process of the test.
The guinea pig ileum longitudinal muscle
The disconnected neck of hartley-Duncan (Hartley-Duncan) male guinea pig is put to death, downcut terminal ileum, flushing, place the Tyrode's sloution of Burn improvement, then longitudinal muscle is cut to the long section of 1-2Cm, sample is placed the tissue bath of Tyrode's sloution of the Burn improvement of oxidation, be warmed to 37 ℃, every muscle specimen all imposes the tension load of 1.0g, continue balance after one hour, add the INDOMETHACIN of 1 μ m in each tissue bath, tissue sample immerses the white corpuscle three rare-D of 60nm concentration after five minutes
4In the solution, the convergent force that each muscle will produce is considered to maximum initial contraction power value.Sample after washing several times in a hour, is added 1 μ m INDOMETHACIN again in each bathtub, again reagent or vehicle are joined in the bathtub after five minutes, after 15 minutes, by the leukotrienes-D that constantly adds up
4Concentration, and obtain a shrinkage curve, current convergent force value and initial convergent force value can be done a contrast, if when reagent reached 100um concentration, the muscular contraction force value was displaced to and LTD
4The right side of relevant contractile response curve just can think that this compound is activated, and the active quantitative survey of antagonist is intact can be according to Arunlakshana and the described PA of Schild
2The method of calculation of value are carried out.(this literary composition is published in Brit.J.Pharmae, Chemotherap.14; 48,1959)
3H-LTD
4Combine with the specific receptors of Guinea pig lung mucous membrane
Put to death male guinea pig, lung is taken out, place ice-cold 50MM, the Tris-HCl damping fluid of PH7.4 is made homogenate with the homogenizer of multi-speed exchanged with lung tissue, 1,000g, 4 ℃, centrifugal ten minutes, take out supernatant, again with 30,000g, 4 ℃, centrifugal 15 minutes, obtain the granule of film, tissue particles is re-suspended into 50MM, the Tris-HCl damping fluid of PH7.6 is hatched for 37 ℃ and was carried out the combination test in 20-40 minute, utilizes vacuum filter to pass through water graceful (Whatman) GF/B glass fiber filter paper, with 3 4ml suction filtration flushings of ice-cold Tris-HCl damping fluid, thereby make bonded
3H-LTD
4With unconjugated
3H-LTD
4Separate, promptly remove unconjugated
3H-LTD
4This process will be finished in eight seconds, has surveyed the intensity of radioactivity on the filter paper again, unlabelled LTD
4Combination when not existing
3H-LTD
4Value deduct and used 2 * 10
7The unmarked LTD of M
4The time bonded
3H-LTD
4Value just obtain specific combination
3H-LTD
4Value.
3H-LTD
4Specificity bonded amount account for the 60-80% of total binding, the resulting compound of the present invention studies show that it can suppress
3H-LTD
4The specificity combination, in these trials, when increasing the concentration of reagent, can seal
3H-LTD
4The specificity combination, can reduce specific combination
3H-LTD
450% o'clock, this concentration was called as IC
5
Show that by above process of the test this time several compounds of invention have special function.Be summarized in following table.The activity of compound changes, and it seems, when the chain of the R-alkyl of inferior tetradecyl compound shortened, its activity also changed thereupon, and this point is also included within the following table:
Compound cavy jejunum Guinea pig lung
(routine number) PA
2(LTD
4) specificity is in conjunction with IC
50UM
10D????9.8????-
10H????9.61????8.7
10F????9.42????-
11????7.87????-
10J????8.26????7.1
10L????8.57????8.0
Biological activity in vivo
The compound of gained of the present invention is to LTD
4Antagonistic action, utilize the Konzett-Rossler method of improvement in the cavy body of anesthesia, to test, particularly after cavy is with vetanarcol anesthesia, carrying out the artificial ventilation by operation with the respirator of fixed capacity tests, when Guinea pig lung is expanded at every turn, surveyed the swelling pressure that produced by respirator, the swelling pressure increase when surpassing baseline, show bronchostenosis.Behind the baseline of determining the swelling pressure, by intravenous injection 50 or 100ng/Kg LTD
4Just can induce bronchial asthma, this is called as first set reaction.When the expansion baseline drops to baseline, to the test compound of cavy injection regulation or the dosage of media, can adopt intravenously administrable or duodenal administration, after intravenously administrable one minute or duodenal administration 5-12 minute, re-inject LTD
4At this moment reaction and first set reaction can be done contrast, the inhibition percentage ratio that this medicine can reach just can be determined, and this result is summarized as follows: the restraining effect value that is obtained by duodenal administration is higher than acquired two times result.
Compound dosage approach suppresses %
Routine number
10F????0.002mg/Kg????i.v.????38
10F????0.0002mg/Kg????i.v.????52
10F????0.02mg/Kg????i.v.????94
10F????0.1mg/Kg????i.d.????74
10F????0.2mg/Kg????i.d.????93
10J????0.5mg/Kg????i.d.????48
10J????1.0mg/Kg????i.d.????53
10I????0.05mg/Kg????i.v.????19
10L????0.5mg/Kg????i.v.????74
10L????1.0mg/Kg????i.d.????25
The resulting compound of the present invention promptly can the separate constituent administration, also can make the mixture administration with other reagent mixture, and they can be used separately, but normally forms preparation with multiple moiety.Its this in other words mixture is made up of the pharmaceutical carrier of routine or thinner and plurality of active ingredients, the formulation of this medicinal composition can be a tablet, lozenge, micellar, pulvis, aerosol, the suspension of water or oil, syrup, the elixir and the aqueous solution that is used to inject, the suitableeest route of administration of this compound is an oral administration.
Certainly, the ratio of the composition of medicine and pharmaceutical carrier or thinner will depend on the route of administration that is adopted, and is promptly oral or without stomach and inhalation route.Oral pharmaceutical usually are tablet, micellar, wherein contain vehicle commonly used, as tackiness agent (as: syrup.Gum arabic, gelatin, Sorbitol Powder, tragakanta or poly-second pyrrolidone), weighting agent (as: lactose, sugar, W-Gum, calcium phosphate, Sorbitol Powder or sweet ammonia), lubricant (as: Magnesium Stearate, talcum powder, polyoxyethylene glycol or silicon), decomposition agent (as: starch) or wetting agent (as: sodium laurylsulfonate).Oral liquid usually is suspension, solution, emulsion, syrup, the ingredients of water or oil, and drying agent perhaps is provided, and water or other suitable reagent are made liquid and re-used before use.This liquid preparation can contain the conventional compound that uses, as suspension agent, spices, thinner or emulsifying agent, as be the medicament or the inhalation of parenteral administration, the medicine that the present invention obtains also can be made into solution or suspension, for example: the aerosol propellant that can be made into suction, make aqueous solution intravenous injection, oil suspension is for intramuscular injection, this compound also can directly spray into lung with dried powder through sucker or miscellaneous equipment, above preparation process of touching upon has explanation in standard textbook, for example: Remington ' s Pharmaceutical Science, Mack publishing company, Easton, Peunsylvania.
Resulting compound of the present invention or its pharmaceutical composition can be used for asthma patient, dosage can reach about 0.1-40mg/kg body weight, one time oral dosage can be near the 0.1-1000mg activeconstituents, repeatedly oral dosage can reach 4000mg/ days activeconstituentss, inhalation lower dosage generally commonly used, promptly be approximately this compound common dose 0.1, the just explanation usually of these dosage, for every specific patient, the physician will be according to patient's basic characteristics, as: the degree of age, body weight, diagnosis, symptom is determined the dosage of administration at last.
Following Example be used for illustrating of the present invention, but they can not be considered to only limit to this.
Embodiment 1
Add 25 gram 4-methyl hydroxybenzoates in the Parr bottle that 150 ml methanol are housed, then, bottle blows off with nitrogen.Add 2.5 grams and contain 5% rhodium that is stated from the aluminium sesquioxide, and, keep vibration constantly simultaneously to reaction mixture 3.74 the atmospheric hydrogen that add 18 hours.Reaction finishes, and reaction system blows off with nitrogen and by diatomite catalyzer removed by filter, and this diatomite washes down with methyl alcohol, takes care not to the catalyzer filter is done.Filtrate is merged, under than demulcent temperature (about 40 ℃), remove methyl alcohol by decompression.Resultant product and aluminium sesquioxide are added in 200 milliliters of ether that contain 3 gram Anhydrous potassium carbonates, sedimentary aluminium sesquioxide and salt of wormwood are removed with diatomite filtration, diatomite washes down with ether, filtrate combines removal of solvent under reduced pressure, just obtain thick product, thick product carries out ball through the Kugelrohr device ball is distilled under 80～100 ℃/about 1mm condition, obtain the 4-hydroxyl hexahydrobenzoic acid methyl esters (98%) of 25.0 grams.
1HNMR（CDCl
3、60MHz）δ3.85（S、1H）、3.65（S、3H）;2.50-1.20（m，10H）。
Embodiment 2
Diatomite with 24 gram oven dry, 11.4 the pyridinium chlorochromate of the sodium acetate of gram and 90.5 grams under agitation, be added in 400 milliliters the anhydrous methylene chloride, the methylene dichloride that adds 350 milliliters again, then, 40 milliliters of methylene dichloride that are dissolved with 44.5 gram 4-hydroxyl hexahydrobenzoic acid methyl esters are injected by addition funnel.After three hours, under agitation, 800 milliliters ether are added, with the silica gel suction strainer of reaction mixture by 250 grams, the solid that obtains is washed four times with ether then.After the filtrate that combines is condensed into green oil, join in 150 milliliters the ether, and then the silica gel suction strainers by 50 grams.Exhausted silica gel washes down with ether, and the filtrate that merges is condensed into edible vegetable oil, distills through Kugelrohr at about 65-85 ℃/1mm again, obtains the 4-oxo hexahydrobenzoic acid methyl esters (97.5%) of 42.6 grams.
1HMR（CDCl
3、60MHz），δ3.70（S、3H），2.9-1.8（9H）。
Embodiment 3
With ice bath 729 milliliters the anhydrous tetrachloro furans and the mixture of 76.4 milliliters of anhydrous diisopropylamines are cooled to 3 ℃, under agitation, with 45 minutes with 340.6 milliliters of hexane solutions that are dissolved with n-Butyl Lithium dropwise add, and continue to stir 15 minutes, then solution are cooled to-75 ℃.By addition funnel, with 20 minutes 269 gram acetaldehyde are closed uncle's fourth imines and dropwise add, continue to stir 30 minutes, temperature remains on-75 ℃, and the clodronic acid diethyl ester of time spent with 47.0 grams adds by addition funnel.Reaction maintains-75 ℃ and continues to stir 1 hour, is warmed up to-11 ℃ then.Drop to-75 ℃ after two hours again, at this moment, 50 milliliters of tetrahydrofuran solutions that will be dissolved with 28.4 gram 4-oxo hexahydrobenzoic acid methyl esters with a hour add by addition funnel, make reaction be warmed up to room temperature and keep a night then.Next day, reactant is poured in the mixture of the oxalic acid, 1.8 premium on currency and the 1.8 liters of toluene that contain 49.0 grams, and vigorous stirring was divided water-yielding stratum after 24 hours, with ether (2 * 500 milliliters) extraction.Toluene-the ether extraction liquid that merges is washed with 5% oxalic acid aqueous solution (2 * 500 milliliters), 500 milliliters of saturated sodium bicarbonates and 500 milliliters of saturated sodium chloride solutions, then organic layer is used the Anhydrous potassium carbonate drying, filtering the back concentrates under vacuumizing, the oily crude product that obtains preparative liquid chromatography (25% ethyl acetate, 300 ml/min, 2 minutes/Cm, twin columns, Rt=7.5 minute) purifying, obtain the 18.5 4-(oxo ethylidenes that restrain)-the hexahydrobenzoic acid methyl esters.
1HNMR（CDCl
3、60MHz）δ10.5（d、1H）5.85（d，1H），3.70（S、3H），2.8-1.5（9H）。
Embodiment 4
4-(oxo ethylidenes with 13.0 grams) the hexahydrobenzoic acid methyl esters is dissolved in 77 milliliters the methyl alcohol, and liquid is cooled to 3 ℃ with ice bath, under vigorous stirring, the sodium borohydride of 3.1 grams was added with 30 minutes in batches, reactant stirred one hour down at 3 ℃, add Glacial acetic acid (1 milliliter) then, reaction is stopped.Under reduced pressure remove methyl alcohol, residuum is poured in 200 milliliters the methylene dichloride, and makes its layering with 400 milliliters water; Tell organic layer, and with 200 milliliters of saturated sodium chloride solutions washings, behind anhydrous sodium sulfate drying, filter and under vacuumizing, concentrate, the oily matter that obtains preparative liquid chromatography (30% ethyl acetate/hexane, 250 ml/min, 2 minutes/Cm, twin columns, Rt=13 minute) purify, obtain the quite pure product of 11.5 grams.Through the Kugelrohr device, under 150～160 ℃/0.8mm condition, carry out ball ball is distilled, obtain the 4-(2-hydroxy ethylidene of 9.03 grams) hexahydrobenzoic acid methyl esters (69%).
1HMNR（CDCl
3、60MHz），δ5.40（t、1H），4.10（d、2H），3.70（S、3H），2.9-1.3（10H）。
Embodiment 5
With dry ice/acetone batch 300 milliliters anhydrous methylene chloride is cooled to-25 ℃ to-30 ℃, under agitation, 12.9 milliliters different third titanium oxide (IV) and one (+) by the 8-9 milliliter-diethyl tartrate are bathed at 100 milliliters of formed solution of methylene dichloride, add by addition funnel successively.After ten minutes, to be dissolved with 8.0 gram 4-(2-hydroxy ethylidenes) 20 milliliters of dichloromethane solutions of hexahydrobenzoic acid methyl esters join in the reaction system, clean beaker and addition funnel with 20 milliliters methylene dichloride, the tert-butylhydroperoxide/toluene solution with 18.4 milliliters of 4.7M adds immediately then.This reaction beaker is placed in the refrigerator, under-20 ℃, leaves standstill 24 hours, reactant is by the silica gel suction strainer then, exhausted silica gel washes down with ethyl acetate/methylene dichloride of 500 milliliter 25%, and the leakage of merging obtains xanchromatic oily matter through vacuum concentration.Thin-layer chromatography (20% ethyl acetate/ethane) analysis revealed of thick product, suitable in the product, anti-diastereomer can separate them with chromatography, the Rf=0.14 of cis diastereomer, the Rf=0.17 of trans diastereomer is through preparative liquid chromatography (10% isopropanol/hexane, 250 ml/min, 2 minutes/Cm, twin columns, trans Rt=16 minute, cis Rt=23 minute) separate and purify, obtain 2.7 gram trans epoxide of buttery and 2.5 gram buttery cis epoxide.The epoxide of cis obtains the 2-(methylol of 0.41 gram for twice with 3% ether/pentane to crystallization)-(3(S)-cis)-1-oxaspiro (2.5)-octane-6-carboxylate methyl ester.Long flat, white crystal, fusing point 67-68 ℃; (α)
20 D-13.3 ° of (C 1.15, chloroform) %ee=＞95%, trans epoxide obtains long, flat, the white crystal of 0.57 gram with ether/pentane recrystallization twice of 30%, and fusing point 31-33 ℃, (α)
20 D-10.6 ° of (C 1.22 chloroforms) %ee=80%, cis epoxidation spy
1HMNR(CDCl
3, 300MHz), δ 3.80(m, 2H), 3.70(S, 3H), 3.10(dd, 1H) 2.00-1.40(9H).
Embodiment 6
0.2 the oxalic acid chlorine of milliliter is added in 27 milliliters the anhydrous methylene chloride, form a mixture, it is cooled to-75 ℃, under agitation dropwise add then with 5 minutes dimethyl alums with 0.35 milliliter, cross the 2-(methylol that will be dissolved with 381 milligrams in 10 minutes)-(3(S)-cis)-3 milliliters of dichloromethane solutions of 1-oxaspiro (2,5)-octane-6-carboxylate methyl ester dropwise add, stir after 20 minutes, again 1.54 milliliters triethylamine was dropwise added with 5 minutes, allow temperature of reaction go back up to room temperature then and continue reaction 45 minutes.Pass through removal of solvent under reduced pressure, the white solid residuum that obtains joins in 50 milliliters the ether, and by the sintered glass funnel filtration, filtrate concentrates under the condition of vacuumizing, and obtains a yellow oil, this thick product preparative liquid chromatography (20% ethyl acetate/hexane, 250 ml/min, 2 minutes/Cm, single-column, Rt=4.75 minute) purify, obtain 355.5mg buttery 2-formyl-(3(S)-cis)-1-oxaspiro (2,5)-octane-6-carboxylic acid formicester.
(α)
20 D+ 132.0 ° (C 0.71, chloroform)
1HNMR(CDCl
3300MHz), δ 9.50(d, 1H), 3.70(S, 3H) 3.20(d, 1H) and, 2.60-1.30(9H).
Embodiment 7
Under agitation 1.80 gram n-tetradecane bases, three phenyl phosphonium bromides are added in 20 milliliters the anhydrous tetrahydro furan, the potassium tert.-butoxide/tetrahydrofuran (THF) with 6.4 milliliters of 0.5M dropwise adds then, and solution becomes orange.To be dissolved with 342 milligrams of 2-formyls-(3(S)-cis after five minutes)-3 milliliters of tetrahydrofuran solutions of 1-oxaspiro (2,5) octane-6-carboxylate methyl ester dropwise add, solution by orange become faint yellow, potassium tert.-butoxide solution with six five equilibriums (0.5 milliliter every part), added portion every 10 minutes, make reaction be tending towards complete.The water that adds 5 milliliters, then reaction mixture is poured in 200 milliliters the ether, this mixture is concentrated to 100 milliliters again with saturated nacl aqueous solution (2 * 100 milliliters) washing under vacuumizing, the hexane that adds 900 milliliters then, muddy liquid is by the silica gel suction strainer.Exhausted silica gel washes down with 500 milliliter of 10% ether/hexane, merging filtrate is condensed into a kind of xanchromatic oily matter under vacuumizing, it is through preparative liquid chromatography (5% ethyl acetate/hexane, 250 ml/min, 2 minutes/Cm, single-column, Rt=5 minute) separate and purify, obtain 527 milligrams of buttery 2-(1-pentadecyls)-(3(S)-(32,3(Z)-6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester, (α)
20 D+ 25.7%(C 0.92, chloroform)
1HNMR(CDCl
3, 3HMHz) δ 5.75(m, 1H), 5.25(t, 1H), 3.70(S, 3H), 3.45(d, 1H), 2.45-1.20(34H).
Use (-)-tartrate diethyl fat, repeat the step of embodiment 5, obtain other two kinds of spirocyclic compounds, these two kinds of compounds and the trans spirocyclic compound that obtains at embodiment 5 react according to the step described in top embodiment 6 and the embodiment 7 respectively.In addition, also replace tetradecyl three phenyl phosphonium bromides with octyl group three phenyl phosphonium bromides, the step of embodiment 7 above repeating, the product that obtains in this method is as follows:
The 2-(1-pentadecyl)-(3(S)-(3 β, 3(Z), 6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.
The 2-(1-pentadecyl)-(3(R)-(3 α, 3(Z), 6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.
The 2-(1-pentadecyl)-(3(R)-(3 β, 3(Z), 6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.
2-(1-nonene base)-(3(S)-(3 α, 3(Z), 6 α))-1-oxaspiro (2,5) octane-6-carboxylate methyl ester.
Embodiment 8
Under agitation, 0.28 milliliter triethylamine is joined with 227 milligrams of 2-(1-pentadecyls)-(3(S)-(3 α, 3 (Z), 6 α))-mixture that 1-oxaspiro (2,5) octane-6-carboxylate methyl ester and 2.7 ml methanol form in, and then add 0.20 milliliter 3-thiohydracrylic acid formicester.After 24 hours, remove methyl alcohol under the decompression, the oil that obtains is joined in 100 milliliters of ether,, with 50 milliliters of saturated sodium-chloride washings, filter and under vacuum, concentrate through anhydrous sodium sulfate drying then again, obtain a kind of xanchromatic oil earlier with 50 milliliters of 0.5N hydrochloric acid.It uses preparative liquid chromatography (10% ethyl acetate/ethane, 250 ml/min, 2 minutes/Cm, single-column, Rt=22 minute) separate and purify, obtain 278.4 milligrams of buttery (4(R)-(1 α, 4 α, 4(Z)))-4-hydroxyl-4-(1-(2-methoxycarbonyl ethyl) sulfo-)-2-cetene base) the hexahydrobenzoic acid methyl esters.(α)
20 D+ 33.5 ° (C0.88, chloroform),
1HNMR(CDCl
3, 300MHz) δ 5.60(m, 1H); 5.4(t, 1H); 3.70(S, 3H); 3.65(S, 3H); 3.60(d, 1H); 2.75(m, 2H); 2.60(m, 2H); 2.20-1.20(34H); 0.89(t, 3H).
Embodiment 9
With (4(R)-(1 α, 4 α, 4(Z)))-4-hydroxyl-4-(1-(2-methoxycarbonyl ethyl) sulfo-)-2-cetene base)) the hexahydrobenzoic acid methyl ester solution is dissolved in 4.0 milliliters the dehydrated alcohol, then, under agitation, 340 milligrams potassium hydroxide pellets are dissolved in 3.3 milliliters the water, formed solution joins in the muddy solution.4.5 after hour, limpid solution with 75 milliliters water towards rare.This aqueous mixture washs with 75 milliliters ether, with the hcl acidifying of 15 milliliters of 0.5N, uses ethyl acetate (3 * 1 milliliters) extraction again.Organic extract liquid anhydrous sodium sulfate drying with merging obtains linen solid with vacuum concentration after filtration.This solid is with 10% ether/hexane recrystallization, obtain (4(R) of 157 milligrams of (64%) white powder-(1 α, 4 α, 4(Z)))-4-(1 ((2-propyloic)-sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.Fusing point is 121-123 ℃; (α)
20 D+ 32.0 ° (C0.95, chloroform),
1HNMR(CDCl
3, 300MHz), δ 5.62(m, 1H); 5.40(t, 1H); 3.62(d, 1H); 2.74(m, 2H); 2.62(m, 2H); 2.25-1.20(34H); 0.89(t, 3H).
This compound has following structural formula:
Embodiment 10A-10M
When selecting suitable oxaspiro and sulfhydryl compound for use, react according to the step of in embodiment 8, being narrated, the ester of generation carries out saponification by the method described in the embodiment 9, obtains following compound:
A. (4(S)-and (1 α, 4 α, 4(Z)))-4-(1-(2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.Fusing point 122-123 ℃; (α)
20 D-38.1 ° (C0.89, chloroform).
1H NMR（CDCl
3，300MHz），δ5.61（m，1H）;5.39（t，1H）;3.62（d，1H）;2.68（m，4H）;2.23-1.22（33H）;0.88（t，3H）。
B. (4(R)-and (1 α, 4 α, 4(Z)))-4-(1-((carboxymethyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
(α)
20 D+ 23.9 ° (C0.66, chloroform).
1H NMR（CDCl
3，300MHz），δ5.69（m，1H）;5.39（t，1H）;3.82（d，1H）;3.21（m，2H）;2.30-1.20（33H）;0.88（t，3H）。
C. (4(S)-and (1 α, 4 α, 4(Z)))-4-(1-((carboxymethyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.(α)
20 D-11.5 ° (C1.42, chloroform).
1H NMR（CDCl
3，300MH
2）δ5.66（m，1H）;5.37（m，1H）;3.82（d，1H）;3.22（m，2H）;2.10-1.12（33H）;0.88（t，3H）。
D. (4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((carboxymethyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid.(α)
20 D+ 3.3 ° (C0.73, chloroform).
1H NMR（CDCl
3，300MH
2）δ5.75（m，1H）;5.44（m，1H）;4.26（d，1H）;3.20（m，2H）;2.40-1.18（33H）;0.88（t，3H）。
E. (4(S)-and (1 α, 4 β, 4(Z)))-4-(1-((carboxymethyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; (α)
20 D-11.8 ° (C0.97, chloroform).
1H NMR（CDCl
3，300MHz）δ5.72（m，1H）;5.49（m，1H）;4.26（d，1H）;3.16（m，2H）;2.50-1.17（33H）;0.88（t，3H）。
F. (4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; (α)
20 D+ 34.8 ° (C0.81, chloroform).
1H NMR（CDCl
3，300MHz）δ5.63（m，1H）;5.41（t，1H）;3.75（d，1H）;2.67（m，5H）;2.09-1.26（33H）;0.88（t，3H）。
G. (4(S)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; (α)
20 D-41.4 ° (C1.26, chloroform).
1H NMR（CDCl
3，300MHz）δ5.63（m，1H）;5.42（t，3H）;3.76（d，1H）;2.67（m，5H）;2.09-1.22（33H）;0.88（t，3H）。
H. (1 α, 4 β, 4(Z)-4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; Fusing point: 71-78 ℃.
1H NMR（CDCl
3，300MHz）δ5.63（m，1H）;5.41（t，1H）;3.76（d，1H）;2.68（m，5H）;2.11-1.26（33H）;0.88（t，3H）。
I. (1 α, 4 α, 4(Z))-4-(1-((3-carboxylic propyl group) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; Fusing point: 71-72 ℃.
1H NMR（CDCl
3，300MHz）δ5.61（m，1H）;5.36（t，1H）;3.59（d，1H）;2.49（m，4H）;2.25-1.20（35H）;0.88（t，3H）。
J. (1 α, 4 β, 4(Z))-4-(1-((3-carboxylic propyl group) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid;
1H NMR (CDCl
3, 300MHz) δ 5.61(m, 1H); 5.41(t, 1H); 3.69(d, 1H); 2.49(m, 4H); 2.10-1.22(35H); 0.88(t, 3H).
K. (1 α, 4 α, 4(Z))-4-(1-((3-((carboxymethyl) amino)-3-oxopropyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid;
1H NMR(CDCl
3, 300MHz) δ 6.85(m, 1H); 5.57(m, 1H); 5.39(t, 1H); 4.27(m, 1H); 4.00(m, 1H); 3.60(d, 1H); 2.90-1.20(37H); 0.89(t, 3H).
L. (1 α, 4 β, 4(Z)-4-(1-((3-((carboxymethyl) amino)-3-oxopropyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; Fusing point: 81.5-82.5 ℃.
1H NMR（CDCl
3，300MHz）δ6.80（S，1H）;5.63（m，1H）;5.42（t，1H）;4.08（d，2H）;3.70（d，1H）;2.85-2.40（m，4H）;2.10-1.20（33H）;0.89（t，3H）。
M. (4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((3-amino-3-oxopropyl) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid; Fusing point: 108-109 ℃; (α)
20 D+ 48.3 ° (C0.86, chloroform).
1H NMR（CDCl
3，300MHz）δ6.02（S，1H）;5.72（S，1H）;5.60（m，1H）;5.45（t，1H）;3.72（d，1H）;2.77（m，2H）;2.58（m，3H）;2.15-1.20（33H）;0.89（t，3H）。
N. (4(R)-and (1 α, 4 β, 4(Z)))-4-(1-((2-propyloic) sulfo-)-2-decene base)-4-ten Scyllite carboxylic acids.
Embodiment 11
In flask, pack into 315 milliliters hexanaphthene, and blow off with nitrogen.Under agitation, add 397 milligrams 2-(1-pentadecyl)-(3(S)-(3 α, 3(Z), 8 α))-diphenyl disulfide of 1-oxaspiro (2.5) octane-6-carboxylate methyl ester and 241 milligrams, make with ice bath and to stir liquid cooling but.With ultraviolet light apart from Jiao on reaction mixture, shone 3.6 hours.Decompression removes down and desolvates, and residuum removes by filter diphenyl disulfide by silica gel (hexane is made eluent), with the ether washing, obtains thick alkene mixture again.Remove ether under the decompression and obtain a kind of xanchromatic oil (suitable/anti-=0.14), it is through preparative liquid chromatography (15% ether/hexane, twin columns, Rt=8 minute) separate, obtain 2-((1-pentadecyl)-(3 α of 120 milligrams of buttery, (E), 6 β))-1-oxaspiro (2.5) octane-6-carboxylate methyl ester.
1H NMR（CDCl
3，300MH
2）δ5.90（m，1H）;5.33（m，1H）;Ja、b＝15.1Hz）;3.68（S，3H）;3.18（d，1H）;2.43（m，1H）;2.10-1.20（32H）;0.89（t，3H）。
The above-mentioned product that obtains joins in five milliliters of round-bottomed flasks that a ml methanol is housed, and under agitation, adds 0.08 milliliter triethylamine, and then adds 0.04 milliliter 3-mercapto-propionate.Two days later, remove and desolvate, thick oil is through stratography (5% ethyl acetate/hexane) fast.Obtain 58.3 milligrams of (84%) buttery (1 α, 4 β, 4(E))-4-hydroxyl-4-(1-((3-methoxyl group-3-oxopropyl) sulfo--2-cetene base)-hexahydrobenzoic acid methyl esters.
1H NMR（CDCl
3，300MHz）δ5.45（m，2H）; 3.69（S，3H）;3.67（S，3H）;3.30（d，2H）;2.80-2.20（m，5H）;2.05-1.20（33H）;0.89（t，3H）。
When above-mentioned ester according to when the step of embodiment 9 is used basic hydrolysis, obtain product (1 α, 4 β, 4(E))-4-(1-((2-propyloic) sulfo--2-cetene base)-4-hydroxyl hexahydrobenzoic acid.
1H NMR（CDCl
3，300MHz，δ5.53（m，2H）;Ja，b，3.37（d，1H）;2.65（m，4H）;2.15-1.20（33H）;0.88（t，3H）。
Claims (7)
1, a kind of method for preparing following formula: compound:
N is one from 0 to 2 a integer in the formula, and R is the straight chained alkyl that contains 6 to 15 carbon atoms, and X is hydrogen atom (when n was 1 or 2, X was also amino), Y be hydroxyl ,-OR
*(R
*Represent low alkyl group) ,-NH
2,-NHR
*,-NR
2 *Or
(R ' be the alkyl or the benzyl of hydrogen atom, 1 to 4 carbon atom), Z be hydroxyl ,-OR
*,-NH
2,-NHR
*Or-NR
2 *
This preparation method is with the epoxide in the following formula
The definition of R is identical with the front in the formula, and Z ' is-OR
*(R
*Represent generation level alkyl) ,-NH
2,-NHR
*, or-NR
2 *
Mercapto-chain alkyl acid derivative with following formula
N is one from 0 to 2 a integer in the formula, and X ' is hydrogen atom (when n was 1 or 2, X is Q-NH-also, and Q is the amido protecting group), and Y ' is-OR
*,-NH
2,-NHR
*,-NR
2 *Or (R ' is the alkyl or the benzyl of hydrogen atom, 1 to 4 carbon atom in the formula), Y ' " is-OR
*,
React in appropriate solvent and under the condition that has alkali to exist, " or Z ' is-OR also can to continue following step again: as Y ', Y '
*The time, " or Z is-those compounds of OH just to obtain Y in the formula, Y ' earlier with strong mineral alkali processing, and then with the strong acid acidifying.
2, the method for preparing following formula: compound according to claim 1.
N is one from 0 to 2 a integer in the formula, and R is the straight chained alkyl that contains 6 to 15 carbon atoms, X be hydrogen atom (when n is 1 or 2, X also-NH
2), Y be hydroxyl ,-OR
*,-NH
2,-NHR
*,-NR
* 2Or
(R ' be the alkyl or the benzyl of hydrogen atom, 1 to 4 carbon atom), Z be hydroxyl ,-OR
*,-NH
2,-NHR
*Or-NR
2 *
This preparation method is with the epoxide in the following formula
The definition of R is identical with the front in the formula, and Z ' is-OR
*,-NH
2,-NHR
*Or-NR
2 *
Mercapto-chain alkyl acid derivative with following formula
N is one from 0 to 2 a integer in the formula, and X ' is hydrogen atom (when n was 1 or 2, X ' is Q-NH-also, and Q is the amido protecting group), and Y ' is-OR
*,-NH
2,-NHR
*,-NR
2 *Or
Be the alkyl or the benzyl of hydrogen atom, 1 to 4 carbon atom, Y ' ' ' is-OR
*)
In suitable solution and under the condition that has alkali to exist, react, also can renew following step: when Y ' Y ' ' ' or Z ' are-OR
*The time, handle earlier with strong inorganic base, use the strong acid acidifying again, obtain Y in the formula, Y ' ' ' or Z and be-those compounds of OH.
3, the method for preparing following formula: compound according to claim 1.
N is one from 0 to 2 a integer in the formula, and R is the straight chained alkyl that contains 6 to 15 carbon atoms, Y be hydroxyl ,-NH
2,-NHR
*,-NR
2 *Or
(R ' be the alkyl or the benzyl of hydrogen atom, 1 to 4 carbon atom).
This preparation method is with the epoxide in the following formula
The definition of R is identical with the front in the formula
Mercapto-chain alkyl acid derivative with following formula
N is one from 0 to 2 a integer in the formula, and Y ' is-OR
*,-NH
2,-NHR
*,-NR
2 *Or
(Y ' ' ' be-OR
*).
In appropriate solvent and under the condition that has alkali to exist, react, also can renew following step: when Y ' or Y ' ' ' are-OR
*The time, handle earlier with strong inorganic base, use the strong acid acidifying again, obtain Y ' in the formula or Y ' ' ' and be-those compounds of OH.
4, according to claim 1 preparation (4(R)-(1 α, 4 β, 4(Z)))-4-(1-(carboxymethyl) sulfo-)-2-cetene base)-method of 4-hydroxyl hexahydrobenzoic acid is: with 2-(1-15 carbene bases)-(3(S)-(3 β, 3(Z), 6 α)-1-oxaspiro (2.5) octane-6-carboxylate methyl ester and the reaction of 2-mercaptoacetic acid methyl esters, react the back and used potassium hydroxide treatment, used hcl acidifying again.
5, according to claim 1 preparation (4(R)-(1 α, 4 β, 4(Z)))-method of 4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid is: with 2-(1-15 carbene bases)-(3 β, 3(Z), 6 α)-1-oxaspiro (2.5) octane-6-carboxylate methyl ester and the reaction of 3-mercapto-propionate, react the back and used potassium hydroxide treatment, used hcl acidifying again.
6, according to claim 1 preparation (4(R)-(1 α, 4 β, 4(Z)))-method of 4-(1-((2-propyloic) sulfo-)-2-cetene base)-4-hydroxyl hexahydrobenzoic acid is: with 2-(1-15 carbene bases)-(3(S)-(3 β, 3(Z), 6 α))-1-oxaspiro (2.5) octane-6-carboxylate methyl ester and the reaction of 3-mercapto-propionate, react the back and used potassium hydroxide treatment, used hcl acidifying again.
7, according to claim 1 preparation (1 α, 4 β, 4(Z))-method of 4-(1-((3-carboxylic propyl group) sulfo-)-2-cetene)-4-hydroxyl hexahydrobenzoic acid is: with 2-(1-15 carbene bases)-(3(S)-(3 β, 3(Z), 6 α)-1-oxaspiro (2.5) octane-6-carboxylate methyl ester and the reaction of 4-sulfydryl methyl-butyrate, react the back and used potassium hydroxide treatment, used hcl acidifying again.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/928,759 US4748274A (en) | 1986-11-07 | 1986-11-07 | 4-hydroxy-4-(substituted alkenyl)cyclohexanecarboxylic acids |
| US928,759 | 1986-11-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87107599A true CN87107599A (en) | 1988-08-03 |
| CN1009088B CN1009088B (en) | 1990-08-08 |
Family
ID=25456699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87107599A Expired CN1009088B (en) | 1986-11-07 | 1987-11-06 | 4-hydroxy-4-(substituted alkenyl)-cyclohexanecarboxylic acids |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4748274A (en) |
| EP (1) | EP0270843B1 (en) |
| JP (1) | JPH07113011B2 (en) |
| KR (1) | KR950005775B1 (en) |
| CN (1) | CN1009088B (en) |
| AT (1) | ATE61352T1 (en) |
| AU (1) | AU595397B2 (en) |
| CA (1) | CA1296740C (en) |
| DE (1) | DE3768449D1 (en) |
| DK (1) | DK583887A (en) |
| ES (1) | ES2036561T3 (en) |
| FI (1) | FI87923C (en) |
| GR (1) | GR3002075T3 (en) |
| HU (1) | HU197880B (en) |
| IE (1) | IE872998L (en) |
| IL (1) | IL84364A (en) |
| NO (1) | NO167382C (en) |
| NZ (1) | NZ222427A (en) |
| PH (1) | PH24148A (en) |
| PT (1) | PT86093B (en) |
| ZA (1) | ZA878217B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102082304B1 (en) | 2013-05-02 | 2020-02-27 | 에스케이케미칼 주식회사 | Copolymer polyester resin and molded product using same |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4622422A (en) * | 1985-08-23 | 1986-11-11 | Merrell Dow Pharmaceuticals Inc. | Cyclohexanealkanoic acids |
-
1986
- 1986-11-07 US US06/928,759 patent/US4748274A/en not_active Expired - Lifetime
-
1987
- 1987-11-02 ZA ZA878217A patent/ZA878217B/en unknown
- 1987-11-02 AU AU80604/87A patent/AU595397B2/en not_active Expired
- 1987-11-02 FI FI874821A patent/FI87923C/en not_active IP Right Cessation
- 1987-11-02 CA CA000550754A patent/CA1296740C/en not_active Expired - Lifetime
- 1987-11-03 NZ NZ222427A patent/NZ222427A/en unknown
- 1987-11-04 IL IL84364A patent/IL84364A/en unknown
- 1987-11-05 ES ES198787116316T patent/ES2036561T3/en not_active Expired - Lifetime
- 1987-11-05 AT AT87116316T patent/ATE61352T1/en not_active IP Right Cessation
- 1987-11-05 DE DE8787116316T patent/DE3768449D1/en not_active Expired - Lifetime
- 1987-11-05 JP JP62278441A patent/JPH07113011B2/en not_active Expired - Fee Related
- 1987-11-05 EP EP87116316A patent/EP0270843B1/en not_active Expired - Lifetime
- 1987-11-06 PH PH36045A patent/PH24148A/en unknown
- 1987-11-06 PT PT86093A patent/PT86093B/en not_active IP Right Cessation
- 1987-11-06 NO NO874627A patent/NO167382C/en unknown
- 1987-11-06 DK DK583887A patent/DK583887A/en not_active Application Discontinuation
- 1987-11-06 IE IE872998A patent/IE872998L/en unknown
- 1987-11-06 KR KR1019870012473A patent/KR950005775B1/en not_active IP Right Cessation
- 1987-11-06 CN CN87107599A patent/CN1009088B/en not_active Expired
- 1987-11-06 HU HU874977A patent/HU197880B/en not_active IP Right Cessation
-
1991
- 1991-06-06 GR GR91400745T patent/GR3002075T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE872998L (en) | 1988-05-07 |
| KR950005775B1 (en) | 1995-05-30 |
| FI87923C (en) | 1993-03-10 |
| NO167382B (en) | 1991-07-22 |
| AU8060487A (en) | 1988-07-28 |
| AU595397B2 (en) | 1990-03-29 |
| IL84364A0 (en) | 1988-04-29 |
| CA1296740C (en) | 1992-03-03 |
| FI874821A (en) | 1988-05-08 |
| GR3002075T3 (en) | 1992-12-30 |
| DK583887A (en) | 1988-05-08 |
| NO167382C (en) | 1991-10-30 |
| NZ222427A (en) | 1989-06-28 |
| ATE61352T1 (en) | 1991-03-15 |
| HU197880B (en) | 1989-06-28 |
| PT86093B (en) | 1990-11-20 |
| JPH07113011B2 (en) | 1995-12-06 |
| ZA878217B (en) | 1988-04-28 |
| IL84364A (en) | 1991-08-16 |
| KR880006186A (en) | 1988-07-22 |
| DK583887D0 (en) | 1987-11-06 |
| EP0270843B1 (en) | 1991-03-06 |
| EP0270843A1 (en) | 1988-06-15 |
| PH24148A (en) | 1990-03-22 |
| JPS63198660A (en) | 1988-08-17 |
| DE3768449D1 (en) | 1991-04-11 |
| HUT45475A (en) | 1988-07-28 |
| FI874821A0 (en) | 1987-11-02 |
| CN1009088B (en) | 1990-08-08 |
| NO874627D0 (en) | 1987-11-06 |
| FI87923B (en) | 1992-11-30 |
| PT86093A (en) | 1987-12-01 |
| ES2036561T3 (en) | 1993-06-01 |
| US4748274A (en) | 1988-05-31 |
| NO874627L (en) | 1988-05-09 |
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